A unified approach to ent-atisane diterpenes and
related atisine and hetidine alkaloids has been developed from ent-kaurane (−)-steviol (1). The conversion
of the ent-kaurane skeleton to the ent-atisane skeleton features a Mukaiyama peroxygenation with concomitant
cleavage of the C13–C16 bond. Conversion to the atisine skeleton
(9) features a C20-selective C–H activation using
a Suárez modification of the Hofmann–Löffler–Freytag
(HLF) reaction. A cascade sequence involving azomethine ylide isomerization
followed by Mannich cyclization forms the C14–C20 bond in the
hetidine skeleton (8). Finally, attempts to form the
N–C6 bond of the hetisine skeleton (7) with a
late-stage HLF reaction are discussed. The synthesis of these skeletons
has enabled the completion of (−)-methyl atisenoate (3) and (−)-isoatisine (4).
Terpenes and alkaloids are ever-growing classes of natural products that provide new molecular structures which inspire chemists and possess a broad range of biological activity. Terpenoid-alkaloids originate from the same prenyl units that construct terpene skeletons. However, during biosynthesis, a nitrogen atom (or atoms) is introduced in the form of β-aminoethanol, ethylamine, or methylamine. Nitrogen incorporation can occur either before, during, or after the cyclase phase. The outcome of this unique biosynthesis is the formation of natural products containing unprecedented structures. These complex structural motifs expose current limitations in organic chemistry, thus providing opportunities for invention. This review focuses on total syntheses of terpenoid-alkaloids and unique issues presented by this class of natural products. More specifically, it examines how these syntheses relate to the way terpenoid-alkaloids are made in Nature. Developments in chemistry that have facilitated these syntheses are emphasized, as well as chemical technology needed to conquer those that evade synthesis.
In the first part of a two-phase pursuit of highly oxidized members of the ent-kaurane and beyerane diterpenoid families, steviol was identified as the ideal cyclase phase terminus. Accordingly, a synthesis of steviol has been developed. This synthesis features a polyene cyclization precursor designed to directly yield oxidation on the axial C19 methyl group. Construction of the necessary [3.2.1]bicyclic system found in the ent-kaurane skeleton was realized with two overbred intermediates. The resulting [3.2.1]bicyclic system undergoes Wagner–Meerwein rearrangement to yield the beyerane skeleton of isosteviol.
Indoleamine
2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase
enzyme implicated in cancer immune response. This account details
the discovery of BMS-986242, a novel IDO1 inhibitor designed for the
treatment of a variety of cancers including metastatic melanoma and
renal cell carcinoma. Given the substantial interest around this target
for cancer immunotherapy, we sought to identify a structurally differentiated
clinical candidate that performs comparably to linrodostat (BMS-986205)
in terms of both in vitro potency and in
vivo pharmacodynamic effect in a mouse xenograft model. On
the basis of its preclinical profile, BMS-986242 was selected as a
candidate for clinical development.
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